U.S. Pat. No. 5,688,792 (hereinafter referred to as the US'792 patent), assigned to Pharmacia & Upjohn Company, discloses a variety of oxazine and thiazine oxazolidinone derivatives and their stereochemically isomeric forms, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. These compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms and acid-fast organisms. Among them, Linezolid, a member of the oxazolidinone class of drugs and chemically named as N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). Linezolid is represented by the following structural formula I:

The main indications of linezolid are infections of the skin and soft tissues and pneumonia (particularly hospital-acquired pneumonia). Linezolid is marketed by Pfizer under the trade names Zyvox (in the United States, United Kingdom, Australia, and several other countries), Zyvoxid (in Europe), and Zyvoxam (in Canada and Mexico).
The synthesis of Linezolid was first described in the US'792 patent. According to the US'792 patent, the Linezolid is prepared by a process as depicted in scheme 1:

The synthesis of Linezolid as described in the US'792 patent involves the following main reaction steps: a) 3-Fluoro-4-morpholinyl aniline is reacted with benzyl chloroformate in the presence of sodium bicarbonate to produce N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline; b) the N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline is reacted with a solution of (R)-glycidyl butyrate in tetrahydrofuran in the presence of n-butyl lithium/hexane at a temperature of −78° C. under nitrogen atmosphere, followed by tedious work-up and isolation methods to produce the (5R)-5-(hydroxymethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone; c) the (5R)-5-(Hydroxymethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone is reacted with methanesulfonyl chloride in the presence of triethylamine in methylene chloride solvent under nitrogen atmosphere to produce (5R)-[[3-[3-fluoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl methane sulfonate; d) (i) the (5R)-[[3-[3-fluoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl methane sulfonate is reacted with sodium azide to produce (5R)-[[3-[3-fluoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl azide, or alternatively (ii) the (5R)-[[3-[3-fluoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl methane sulfonate intermediate is reacted with potassium phthalimide to produce (S)—N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide; e) (i) the (5R)-[[3-[3-fluoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl azide intermediate is hydrogenated in the presence of 10% palladium/carbon to produce (S)—N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, or (ii) the (S)—N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide intermediate is then reacted with aqueous methyl amine to produce (S)—N-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl-methyl amine; and f) the (S)—N-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl-methyl amine intermediate is then subjected to acetylation with acetic anhydride to produce Linezolid.
The processes for the preparation of Linezolid as described in the aforementioned prior art suffer from several disadvantages and limitations. The main disadvantage of the prior art processes is that the reaction between N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline and (R)-glycidyl butyrate in tetrahydrofuran in the presence of n-butyl lithium/hexane should be performed at extremely low temperatures (−78° C.) under very strict control of reaction conditions; processes involving extreme low temperatures are undesirable for large-scale operations since they require special equipment and an additional reactor, adding to the cost, thereby making the processes commercially unfeasible.
Various processes for the preparation of Linezolid, its intermediates, and related compounds are described in U.S. Pat. No. 5,837,870, U.S. Pat. No. 5,880,118, U.S. Pat. No. 6,107,519, U.S. Pat. No. 6,362,334, U.S. Pat. No. 6,887,995, U.S. Pat. No. 7,429,661, U.S. Pat. No. 7,307,163 and U.S. Pat. No. 7,291,614; PCT Publication Nos. WO 99/24393, WO 2007/116284, WO 2009/063505, WO 2010/031769, WO 2010/081404, WO 2010/084514, WO 2011/077,310, WO 2011/137222 and WO 2012/114355; Chinese Patent Application Publication No. CN 1772750; and Journal Articles: J. Med. Chem. 39(3), 673-679, 1996; Tetrahedron Lett., 40(26), 4855, 1999; and Organic Letters 2003, 5, 963-965.
According to the U.S. Pat. No. 5,837,870 (hereinafter referred to as the US'870 patent), the Linezolid is prepared by a process as depicted in scheme 2:

As stated in the preceding paragraphs, the processes for the preparation of Linezolid as disclosed in the prior art were tedious and cumbersome—for example, U.S. Pat. No. 5,837,870 describes a process for the preparation of (5R)-5-(hydroxymethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone intermediate wherein, tetrahydrofuran is mixed with t-amyl alcohol, followed by the addition of butyl lithium in hexanes with agitation to produce a lithium t-amylate mixture, which is then added to solution of N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline [obtained as per the process described in J. Med. Chem., 39(3), 673 (1996)] in tetrahydrofuran while maintaining the temperature at less than 8° C. and rinsed in with tetrahydrofuran to produce a lithium anion mixture. Tetrahydrofuran is mixed with S-(+)-3-chloro-1,2-propanediol, the resulting mixture is cooled to −16° C., followed by the addition of potassium t-butoxide in tetrahydrofuran while maintaining the temperature at less than −10° C. The resulting slurry is then stirred at −14° C. to 0° C. for 1 hour and then added to the lithium anion mixture while maintaining both mixtures at 0° C., then rinsed in with tetrahydrofuran. The resulting slurry is stirred for 2 hours at 20-23° C. and then cooled to 6° C., followed by the addition of a mixture of citric acid monohydrate in water. The resultant liquid phases are separated and the lower aqueous phase is washed with ethyl acetate. The organic layers are combined and solvent is removed under reduced pressure. Heptane and water are added to the resulting mass and the solvent is removed by reduced pressure until a total volume of 5 ml remains. The precipitated product is collected by vacuum filtration and washed with water and then dried in a stream of nitrogen to produce (5R)-5-(hydroxymethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone.
Organic Letters 2003, 5, 963-965 describes a process for the preparation of Linezolid as depicted in scheme 3:

U.S. Pat. No. 6,107,519 (hereinafter referred to as the US'519 patent) describes various processes for the preparation of Linezolid as depicted in schemes 4 & 5:


PCT Publication No. WO 2012/114355 describes a process for the preparation of Linezolid as depicted in scheme 6:

The processes for the preparation of Linezolid as described in the aforementioned prior art suffer from the following disadvantages and limitations:    a) the prior art processes involve the use of highly flammable and dangerous reagents like n-butyl lithium in hexanes;    b) handling of n-butyl lithium is very difficult at lab scale and in commercial scale operations;    c) the reaction between N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline and (R)-glycidyl butyrate in tetrahydrofuran in the presence of n-butyl lithium/hexane should be performed at extremely low temperatures (−78° C. to −16° C.) under very strict control of reaction conditions; processes involving extremely low temperatures are undesirable for large-scale operations since they require special equipment and an additional reactor, adding to the cost, thereby making the processes commercially unfeasible;    d) the processes require longer reaction times and the yields and purity of the product obtained is very low;    e) the processes involve the use of expensive reagents including noble metal catalysts such as palladium on charcoal; and expensive chiral reagents such as (±)-trans-1,2-diaminocyclohexane, in excess amounts, for preparing the starting material 5-(tetrahydro-pyran-2-yloxymethyl)-2-oxazolidinone which is difficult to synthesize;    f) the processes involve the use of tedious and cumbersome procedures like prolonged reaction time periods, multiple process steps, column chromatographic purifications, multiple isolation/re-crystallizations—methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible;    g) the processes involve the use of multiple and excess amounts of hazardous solvents like n-hexane, heptanes, dioxane and tetrahydrofuran;    h) the processes involve the use of highly toxic reagents like phosgene, triphosgene, pyridinium p-toluenesulfonate, pyridine and sodium azide;    i) methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible;    j) the overall processes generate a large quantity of chemical waste which is difficult to treat.
The major drawback of the processes for the preparation of linezolid described in the aforementioned prior art is that the processes involve the use of highly flammable, corrosive and pyrophoric reagents like n-butyl lithium in hexanes, thereby requiring very strict control of reaction conditions at low temperatures (−78° C. to −16° C.). Handling of n-butyl lithium is very difficult at lab scale and in commercial scale operations. Moreover, the yields and purities of the product obtained according to the prior art processes are very low.
Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of (5R)-5-(hydroxymethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone at lab scale and in commercial scale operations.
U.S. Pat. No. 7,307,163 B2 (hereinafter referred to as the US'163 patent), assigned to Symed Labs Limited (the present applicant), discloses a novel and commercially viable process for the preparation of Linezolid as depicted in scheme 7:

U.S. Pat. No. 7,429,661 B2 (hereinafter referred to as the US'661 patent), assigned to Symed Labs Limited (the present applicant), discloses a novel and commercially viable process for the preparation of Linezolid as depicted in scheme 8:

However, a need remains for an improved, commercially viable, cost effective and environmentally friendly process of preparing Linezolid with high yield and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation. Desirable process properties include non-hazardous conditions, environmentally friendly and easy to handle reagents, reduced cost, greater simplicity, increased purity, and increased yield of the product, thereby enabling the production of Linezolid, in high purity and with high yield.